Mammals generate immune responses through a complex interplay among various cell types controlled by genes of the major histocompatibility complex (MHC). Thus, in the mouse, genes encoded by the I-region control the interactions of T cells with macrophages and B cells that are required to produce optimal humoral and cellular immune functions. Diverse studies strongly suggest that proteins known as Ia (I-region-associated) antigens present on the surfaces of B cells and macrophages and encoded by genes of the I-region are involved in these cooperative interactions. To gain insight into how the structure of murine Ia antigens relates to their function, we propose to: 1) determine the degree and nature of structural variation among allelic forms of Ia antigens, and 2) determine whether allelic differences are restricted to one or more regions of these molecules. We propose to use methods that have proven highly successful in analyzing other membrane products of the murine MHC.